Arylacetylphenyl chloroformates



United States Patent 3,293,972 ARYLACETYLPHENYL CIHJOROFORMATES EdwardL. Schumann, Portage, Mich, assignor to The Upgohn Company, Kalamazoo,Mich, a corporation of Delaware No Drawing. Original application Mar.18, 1963, Ser. No. 266,959. Divided and this application Apr. 29, 1964,Ser. No. 363,617

3 Claims. (Cl. 260-463) This application is a division of my co-pendingapplication, Serial No. 266,089, filed March 18, 1963.

This invention relates to new and useful chemical compounds and moreparticularly to phenylacetylphenyl chloroformates which are useful asintermediates in the preparation of phenylacetylphenyl carbamates, whichin turn are useful as sedatives and anti-inflammatory agents.

The novel compounds of the present invention are represented by thefollowing structural formulas:

i (H) O-G-Gl CH C Y Y X X (I) and t? Rz\ IOI 0-0-01 CHG R4 X X (II)where in each of X and Y is from zero to 3 alkoxys of from 1 to 2 carbonatoms, inclusive; X is selected from the group consisting of from zeroto 2 halogens and from zero to 2 alkyls of from 1 to 3 carbon atoms,inclusive; and Y is selected from the group consisting of from zero to 1halogen, from zero to 1 nitro, and from zero to 1 methyl; and R and Rare selected from the group consisting of phenyl, tolyl, andmethoxyphenyl.

The starting material for the preparation of the compounds of thepresent invention is a hydroxyacetophenone of the formula:

I Y Y X X X (N) (III) and ice one, benzene, diethyl ether, and the like.This reaction is exothermic and is advantageously carried out attemperatures between about 30 C. and about +30 C. The phosgenezorganicsolvent solution is added slowly and with mixing to prevent localizedheating or undesirable temperatures above 30 C. The chloroformate, thusformed, accumulates in the organic phase and the aqueous phase isseparated. The chloroformate can be isolated and purified byconventional techniques, e.g., by recrystallization, distillation, etc.,or it can be used without further purification in the preparation of thephenylacetylphenyl carbamates referred to above (see Formulas V and VIbelow).

On reaction of the chloroformates of Formulas I and II With ammonia oran amine of the formula R1 HN compounds of the following formulas areobtained:

0 R1 0 O- N QmHFL R,

Y Y X X (V) and 0 R1 R3 O( lN CH J- Rz R.

X X I) wherein R and R taken individually represent a member selectedfrom the group consisting of hydrogen, alkyl of from 1 to 4 carbonatoms, inclusive, and alkenyl of from 3 to 4 carbon atoms, inclusive,and taken together with N represent saturated heterocyclic aminoselected from the group consisting of unsubstituted and monoandpolyallryl substituted piperidino, morpholino, thiamorpholino,pyrrolidino, hexamethylenirnino, heptamethylenimino, octamethylenimino,and homomorpholino wherein each alkyl is of from 1 to 4 carbon atoms,inclusive, and R R X, X, Y, and Y are as hereinbefore defined.

The reaction of ammonia or the amine With the chloroformate is carriedout in the presence of a solvent, for example, water, diethyl ether, anddioxane. The reaction is advantageously carried out at temperatures inthe range of about 10 C. to about C. The rate of reaction is slow attemperatures below abou 10 C.; and at temperatures above about 50 C.,the ammonia or amine can volatilize and decomposition of thechloroformate intermediate or carbamate product can occur.Stoichiometrically, the reaction requires one mole of amine for eachmole of chloroformate. However, the reaction produces one moleofhydrogen chloride, so an excess of ammonia or the amine, preferablyabout at least one mole excess, or another suitable acid acceptor, forexample, triethylarnine, pyridine, picoline, sodium hydroxide, and thelike should be employed. The carbamate product of Formula V or VI isrecovered by conventional methods, for example, filtering ofi anysolids, removing the solvent, washing and recrystallization from asuitable solvent.

Representative groups within the scope of the present invention include:alkyl, e.-g., methyl, ethyl, propyl, isopropyl, butyl, and isobutyl;alkenyl, e.g., allyl, methallyl, and crotyl; halogen, e.g., fluoro,chloro, bromo, and iodo; saturated heterocyclic amino, e.g., piperidine,morpholino, thiamorpholino, pyrrolidino, hexamethylenimino,heptamethylenimino, octamethylenimino, homomorpholino,Z-methylhexamethylenimino, 2,2-dibutylhexamethylenimino,3,6-dimethylhexamethylenimino, 2- ethylmorpholino,Z-ethyl-S-methylmorpholino, 3,3-dimethylmorpholino,3-methylthiamorpholino, 2,3,5,6-tetramethylthiamorpholino,2,3,-trimethylthiamorpholino, 2- methylpiperidino, 3-methylpiperidino,4-methylpiperidino, Z-butylpiperidino, 2-propylpiperidino,4-isopropylpiperidino, 3,4 diethylpiperidino, 2-sec.butylpyrrolidino,2,2 dimethylpyrrolidino, Z-ethylpyrrolidino, 3,4-dimethylpyrrolidino,and 2-isopropylpyrrolidino; and alkoxy, e.g., methoxy and ethoxy.

The starting hydroxyacetophenones of Formulas III and 1V can be preparedby a Friedel-Crafts reaction between a phenol of the formula:

X X (VII) wherein X and X are as hereinbefore defined, and an acidhalide of the formula:

II CHz-C-Hal Y Y' (VIII) and CH( i-Ha.l Rr

wherein Hal is chlorine or bromine, and R R Y, and Y are as hereinbeforedefined.

The following examples are illustrative of the preparation of compoundsof the present invention but are not to be construed as limiting.

Example 1.2-phenylacetylplzerzyl dimethylcarbamate A.2-phenylacetylphenyl chloroformate: 42.4 grams (0.2 mole) of2'-hydroxy-2-phenylacetophenone and 8.0 grams (0.2 mole) of sodiumhydroxide are added to 150 ml. of water. To this aqueous solution isadded a solution of 19.8 grams (0.2 mole) of phosgene in 120 ml. oftoluene, prepared by bubbling phosgene into toluene at C. Thephosgeneztoluene solution is added slowly with mechanical stirring whilemaintaining the temperature below C. The reaction mixture is stirred for1.5 hours and filtered to remove solids. The aqueous layer is separatedfrom the organic layer in a separatory funnel and the organic layerwashed with ZOO-ml. portions of 5% aqueous potassium hydroxide solution.The toluene solution is Washed with water until neutral and then driedover anhydrous sodium sulfate. The toluene is removed by distillationunder reduced pressure to leave Z-phenylacetylphenyl chloroformate as aresidue.

B. Z-phenylacetylphenyl dimethylcarbamate: To a solution of 27.4 grams(0.1 mole) of Z-phenylacetylphenyl chloroformate in 200 ml. of anhydrousdiethyl ether is added 9.0 grams (0.2 mole) of dimethylamine dissolvedin 100 ml. of anhydrous ether. The reaction flask is stirred during theaddition to prevent localized heating. The reaction mixture is allowedto stand overnight during which time a precipitate forms. Theprecipitate is .removed by filtration and the ether by means ofdistillation under reduced pressure to provide Z-phenylacetylphenyldimethylcarbamate.

Example 2.3,5-dimeth0xy-4-(4-meth0x3 phenylacetyl)-2-metlzylplzenylcarbamate Following the procedure of Example 1, part A, substitut ing2",6 dimethoxy 4' hydroxy-Z-( t-methoxyphenyl)- 3'-methylacetopl1enor1efor the 2-hydroxy-Z-phenylacetophenone, the respective chloroforrnate isobtained. Following the procedure of part B, commencing with3,5-dimethoxy-4- (4-methoxyphenylacetyl) -2-methylphenyl chlorotormateand substituting ammonia for dimethylamine, 3,5-dimethoxy-4-(4-methoxyphenylacetyl) Z-methylphenyl carbamate isobtained.

Example 3.-2,3-dimetlz0xy-6- (3,4-dimeth0xyphenyl) acetyl-phenylmetllylallycarbamate Following the procedure of Example 1, part A,substituting 3,4'-dimethoxy-2-(3,4-dimethoxyphenyl)2-hydroxy-acetophenone for the 2'-hydroxy-2-phenylacetophenone, therespective chloroformate is obtained. Following the procedure of part B,commencing with 2,3-dimethoxy- 6- 3 ,4-dimethoxyphenylacetyl -phenylchloroformate and substituting methylallylamine for dimethylamine,2,3-dimethoxy-d- 3,4-dimethoxyphenylacetyl phenyl methallylcarbamate isobtained.

Example 4.3,4-dietlzoxy-2-(3-etlz0xy-5-metlzoxyplzenylacetyl)-phenylmethyletlzyl carbamate Following the procedure of Example 1, part A,substituting 2',4-diethoxy-2-(3-ethoxy-5-methoxyphenyl)-6'-hydroxyacetophenone for the 2-hydroxy-2-phenylacetophenone, therespective chloroformate is obtained. Following the procedure of part B,commencing with 3,5-diethoxy-2(3-ethoxy-S-methoxyphenylacetyl)-phenylchloroformate and substituting methylethylamine for dimethylamine,3,5-diethoxy-2-(3-ethoxy S-methoxyphenylacetyl)phenylmethylethylcarbamate is obtained.

Example 5 .-5 -meth0xy-2-(3-chl0r0-2,4,6-trimethoxyplzenylacetyl)phenyldicrotylcarbamate Example 6.4-metlzyl-Z-phenylacetylphenyltetramethylenecarbamate Following the procedure of Example 1, part A,substituting 2-hydroxy-5-methyl-2-phenylacetophenone for the2-hydroxy-2-phenylacetophenone, the respective chloroformate isobtained. Following the procedure or" part B, commencing with4-methyl-2-phenylacetylphenyl chlorofromate and substituting pyrrolidinefor dimethylamine, 4-methyl-2 phenylacetylphenyl tetramethylenecarbamateis obtained.

Example 7.3-metlzyl-4-phenylacetylphenyl pentamethylenecarbamateFollowing the procedure of Example 1, part A, substituting4-hydroxy-2'-methyl-2-phenylacetophenone for the2-hydroxy-2-phenylacetophenone, the respective chloroformate isobtained. Following the procedure of part B, commencing with3-methyl-4-phenylacetylphenyl chloroformate and substituting piperidinefor dimethylamine, 3-methyl-4-phenylacetylphenyl pentamethylenecarbamateis obtaiend.

Example 8.2-flu0r0-4-plzenylacetylphenyl lzexamet/zylenecarbamateFollowing the procedure of Example 1, part A, substituting3-iiuoro-4-hydr0xy-2-phenylacetophenone for the2'-hydroxy-2-phenylacetophenone, the respective chloroformate isobtained. Following the procedure of part B, commencing withZ-fiuoro-4-phenylacetylphenyl chloroformate and substitutinghexarnethylenimine for dimethylamine, 2-fiuoro-4 phenylacetyphenylhexamethylenecarbamate is obtained.

Example 9.2- (2,5-dimetlzoxyplzenylacetyl) -3,4,5- zrimethoxyplzenyll2eptamethylenecarbamate Following the procedure of Example 1, part A,substituting 2-(2,5-dimethoxyphenyl)-6'-hydroxy2',3,4-trimethoxyacetophenone for the 2-hydroxy-2-pheny1acetophenone,the respective chloroformate is obtained. Following the procedure ofpart B, commencing with 2-(2,5- dimethoxyplienylacetyl)-3,4,5trimethoxyphenyl chloroformate and substituting heptamethylenimine fordimethylamine, 2-(2,S-dimethoxyphenylacetyl)-3,4,5-trimethoxyphenylheptamethylenecarbamate is obtained.

Example 10.-3,5-diethxy-2- (4-etlz0xyphenylacetyl) 4-metlz0xyphenyloctam etlzylenecarbamate Following the procedure of Example 1, part A,substituting 2,4 diethoxy-Z-(4-ethoxyphenyl)-6'-hydroxy-3-methoxyacetophenone for the 2'-hydroxy-2-phenylacetophenone, therespective chloroformate is obtained. Following the procedure of part B,commencing with 3,5-di ethoxy 2 (4 ethoxyphenylacetyl) 4 methoxyphcnylchloroformate and substituting octamethylenimine for dimethylamine,3,5-diethoxy2-(4-ethoxyphenylacetyl)-4- methoxyphenyloctamethylenecarbamate is obtained.

Example 1] .4-(4-eth0x7phenylacetyl) phenyl (1 ,1-dimethyltetramethylene carbamate Following the procedure of Example 1,part A, substituting 2-(4-ethoxyphenyl) 4 hydroxyacetophenone for the2'-hydroxy-2-phenylacetophenone, the respective chloroformate isobtained. Following the procedure of part B, commencing with4-(4-ethoxyphenylacetyl)phenyl chloroformate and substituting2,2-dimethylpyrrolidine for dimethyiamine,4-(4-ethoxyphenylacetyl)phenyl (1,1- dimethyltetramethylene)carbamate isobtained.

Example 12.-3,5-dietlz0xy-2-(4-etlzoxy-3-mellzoxyphenylacetyl) phenyl (1-nzetlzylpentametlzylene) carbamate Following the procedure of Example1, part A, substituting 2',4 diethoxy-Z-(4-ethoxy-3-methoxyphenyl)-6'-hydroxyacetophenone for the 2-hydroxy-2-phenylacetophenone, therespective chloroformate is obtained. Following the procedure of part B,commencing with 3,5-diethoxy 2 (4 ethoxy 3 methoxyphenylacetyl)phenylchloroformate and substituting Z-methylpiperidine for dimethylamine,3,5-diethoxy-2-(4-ethoxy-5-methoxyphenylacetyl)pheny1(l-methylpentamethylene) carbam ate is obtained.

Using the following hydroxyacetophenones in Examples 1 through 12, partA, the corresponding chloroformates are obtained:

4-chloro-2'-hydroxy-2-phenyl-,

5 '-chloro-2'-hydroXy-2-phenyl-,

4,6-dimethoxy-2- (2,3 -dimethoxyphenyl -2.-hydroxy-,

4,6'-dimethoxy-2-hydroxy-2- (Z-methoxyphenyl) 4,6'-dimethoxy-2-hydroxy-2- (4-methoxyphenyl) 4',6'-dimethoxy-2'-hydroxy-2-(4-methoxyphenyl) -3 methyl-,

4', 6'-dimethoxy-2'-hydroxy-2- (Z-methoxyphenyl) -3 methyl-,

2',4-dimethoxy-6'-hydroxy-2- (4-methoxyphenyl) -3 methyl-,

2',4-dimethoxy-6 '-hydroxy-2- (Z-methoxyphenyl -3 methyl-,

4',6'-dimethoXy-2'-hydroxy-3 -methyl-2-phenyl-,

3 ,4-dimethoxy-2'-hydroxy-2-phenyl-,

4',6'-di1nethoxy-2'-hydroxy-2-phenyl-,

3 '-hydroxy-5'-isopropyl-6'-methoxy-2'-methyl-2-pheny1-,

2'-hydroxy-4'-methoxy-2- (2-m ethoxyphenyl 2'-hydroxy-4'-methoxy-2-(4-methoxyphenyl 6 6'-hydroxy-2-(2-methoxypheny1)-2,3 ',4'-trimethoxy-,2-hydroxy-5-methoxy-2-phenyl-, 2-hydr0xy-6'-methoxy-2-phenyl-, and2'-hydroxy-4'-methoxy-Z-phenylacetophenones.

In following the procedures of Examples 1 through 12, part B, using theabove chloroformates, the corresponding carbamates are also obtained.

mate is obtained. Following the procedure of part B,

commencing with 4-phenylacetylphenyl chloroformate and substitutingmorpholine for dimethylarnine, 4-phenylacetylphenyl(3-oxapentamethylene)-carbarnate is obtained.

Example J4.4-plzenylacezylplzenyl (3-thiapentamethylene -carbamateFollowing the procedure of Example 13, part B, commencing with4-phenylacetylphenyl chloroformate and substituting thiamorpholine formorpholine, 4-phenylacetylphenyl (3-thiapentamethylene)carbamate isobtained.

Example 15.4-phenylacetylphenyl (3 -0xal1examethylene) -carbamateFollowing the procedure of Example 13, part B, commencing with4-phenylacetylphenyl chloroformate and substituting homomorpholine formorpholine, 4-phenylacetylphenyl (3-oxahexamethylene)carbamate isobtained.

Following the procedure of Example 1, part A, substituting the2'-hydr0xy-2phenylacetophenone by 2,2-diphenyl-4-hydroxyacetophenone,2,2-diphenyl-2-hydroxy acetophenone,2,2-di-p-tolyl-2-hydroxyacetophenone, and 2,2-di-4-methoxyphenyl-2'-hydroxy 4 methoxyacetophenone, the corresponding4-diphenylacetylphenyl, Z-diphenylacetylphenyl,2-(di-p-tolylacetyl)phenyl, and 2-(di- 4 methoxyphenylacetyl) 5methoxyphenyl chloroformates are obtained, which by the procedures ofpart B of Examples 2, 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13, andExamples 14 and 15, are converted to the corresponding unsubstitutedcarbamates and dimethyl-, methylallylmethylethyl-, dicrotyl-,tetramethylene-, pentamethylene-, hexamethylene-, heptamethylene-,octamethylene-, (1,1- dimethyltetramethylene)-, (1methylpentamethylene)-, (3-oxapentamethylene)-, (3-thiapentamethylene)-,and (3- oxahexamethylene) carbamates.

The carbamates of the invention have demonstrated anti-inflammatoryactivity as shown by the granuloma pouch technique in rats and providethe veterinarian with a method for treating inflammation in large andsmall animals as well as birds and poultry. The animals and birds can becommercial animals raised for profit as Well as animals kept for pets orresearch. Inflammatory conditions which can be treated include, but arenot limited to, enteritis, iritis, retained placenta, laminitis,rheumatoid and traumatic arthritis, osteoarthritis, periostitis,tendonitis, tenosynovitis, bursitis, and myositis.

What is claimed is:

1. A compound selected from the group consisting of compounds of theformula:

if fl) OCCl H g Y Y XX 1 and of the formula:

0 Bi (H) oHll-cl X X (II) wherein each of X and Y is from zero to 3alkoxys of 2. 4-phenylacetylphenyl chloroformate.

from 1 to 2 carbon atoms, inclusive; X is selected from 3- -diphenylaetylphenyl hl roformate.

the grou; cloliislistingfof frolm zero tob2 halogens and1 fromReferences Cited by the Examiner zero to a y s of term to 3 car onatoms, inc usive;

Y is selected from the group consisting of from zero UNITED STATESPATENTS to 1 halogen, from zero to 1 nitro, and from zero to 1 2,455,65212/43 Britney et a1 2,496,091 1/50 Hammond 260-463 methyl; and R and Rare selected from the group consisting of phenyl, tolyl, andmethoxyphenyl. CHARLES E. PARKER, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 203,972 August 31 1965 Edward L. Schumann It is hereby certified that errorappears in the above numbered patent requiring correction and that thesaid Letters Patent should read as corrected below.

Column 1, line 34, for '!where in" read wherein column 2, line 52, for"abou" read about column 4, lines 8 and 9, for"(3,4-dimethoxyphenyl)acetyl-phenyl", in italics, read(3,4-dimethoxyphenylacetyl)-phenyl in italics; column 4, line 64, for"obtaiend" read obtained column 6, line '43, for "methylallyl-"readmethylallyl-, lines 70 to 75, the formula should appear as shown belowinstead of as in the patent:

Signed and sealed this 10th day of May 1966 (SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA: